1. Field Of The Invention
The invention relates to the production of optically-pure 2,2-dimethylcyclopropane-carboxylic acid by resolution of its racemates.
2. Background Art
2,2-Dimethylcyclopropanecarboxylic acid is an important intermediate product for the synthesis of enzyme inhibitor cilastatin (European Patent No. 0,048,301) and of insecticides of the pyrethrin type (British Patent No. 1,260,847), respectively.
In particular for the production of pharmaceutical active ingredients, it is desirable to have available 2,2-dimethylcyclopropanecarboxylic acid in optically pure form, i.e., in the form of pure (S)-(+)- or pure (R)-(-)-enantiomers. Since the chemical synthesis of 2,2-dimethylcyclopropanecarboxylic acid provides the compound in the form of its racemate, it is necessary to perform a resolution of this racemate. Such resolutions of racemates are usually brought about in that the enantiomer mixture to be separated first is converted to a mixture of diastereomeric derivatives by an optically active auxiliary substance, which can be separated because of the different physical properties of the diastereomers by fractionating crystallization or chromatography. From the diastereomers thus separated, a pure enantiomer of the compound to be separated and the optically active auxiliary substance is then ideally set free in each case.
In reality, with a given auxiliary substance, even though such substance is optically completely pure, in most cases only the incomplete separation of one pure enantiomer is possible, so that a mixture remains, which mainly consists of the other enantiomer. In less advantageous cases, neither of the two enantiomers can be isolated in pure form. As derivatives of carboxylic acids for the purpose of the resolution of racemates, their salts with optically active bases, in particular amines, are often used. These salts have the advantage that they are formed very easily and quickly and can also be cleaved again by adding a strong acid. For resolution of racemates of 2,2-dimethylcyclopropanecarboxylic acid, (S)-(-)-1-phenylethylamine (British Patent No. 1,260,847), (-)-N-methylephredrine (Japanese Published Patent Application Nos. 60-56936 and 60-56942), quinine (European Published Patent Application No. 0,161,546) and various 1,2-diphenylethylamines (European Published Patent Application No. 0,093,511) have already been used.
With 1-phenylethylamine, neither a satisfactory yield nor a sufficient optical purity was able to be achieved. Quinine yielded an enantiomer in good optical purity, but in poor yield, no yield was indicated for N-methylephedrine. In the case of 1,2-diphenylethylamine, the yield is satisfactory and the optical purity is very good, but the reagent, as also is N-methylephedrine, is very expensive.
Further, it is known that 2,2-dimethylcyclopropanecarboxylic acid can be separated in the enantiomers via the diastereomeric menthyl esters, which are obtainable from the acid chloride with (+)- or (-)-menthol (U.S. Pat. No. 4,487,956). This process does provide usable yields and optical purities, but is relatively complicated in the working-up and requires the use of the relatively expensive menthol.